TY - JOUR T1 - Ryanodine Receptor 2 Contributes to Impaired Protein Localization in Cyclic Nucleotide-gated Channel Deficiency JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0119-19.2019 SP - ENEURO.0119-19.2019 AU - Hongwei Ma AU - Fan Yang AU - Michael R Butler AU - Jacob Rapp AU - Yun-Zheng Le AU - Xi-Qin Ding Y1 - 2019/06/10 UR - http://www.eneuro.org/content/early/2019/06/10/ENEURO.0119-19.2019.abstract N2 - The photoreceptor cyclic nucleotide-gated (CNG) channel plays a pivotal role in phototransduction and cellular calcium homeostasis. Mutations in the cone photoreceptor CNG channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophies. CNG channel deficiency leads to endoplasmic reticulum (ER) stress-associated cone apoptosis, protein mislocalization, and ER calcium dysregulation. This work investigated the potential mechanisms of protein mislocalization associated with ER calcium dysregulation using Cnga3-/- mice lacking ER Ca2+ channel ryanodine receptor 2 (RyR2) specifically in cones. Deletion of Ryr2 improved outer segment (OS) localization of the cone proteins M-opsin, S-opsin, and cone phosphodiesterase subunit α’ (PDE6C) and decreased inner segment localization. One-month-old Cnga3-/- mice showed approximately 30% of M-opsin, 55% of S-opsin, and 50% of PDE6C localized to the OS. Cnga3-/- mice with Ryr2 deletion at the same age showed almost 60% of M- opsin, 70% of S-opsin, and 70% of PDE6C localized to the OS. Deletion of Ryr2 nearly completely reversed elevations of the ER stress markers phospho-IRE1α and phospho-eIF2α and suppressed cone apoptosis. Consistent with the improved cone protein localization and reduced ER stress/cone apoptosis, cone survival was improved by deletion of Ryr2. The number of cones was increased by about 28% in 2-4 month-old Cnga3-/- mice with Ryr2 deletion, compared with age-matched Cnga3-/- mice. This work demonstrates a role of RyR2/ER calcium dysregulation in protein mislocalization, ER stress and cone death. The findings provide novel insights into the mechanisms of photoreceptor degeneration and support strategies targeting ER calcium regulation to manage retinal degeneration.Significance Statement The cyclic nucleotide-gated (CNG) channel plays a pivotal role in phototransduction and photoreceptor calcium homeostasis. Mutations in the cone CNG channel subunits are associated with achromatopsia and cone dystrophies. CNG channel deficiency leads to endoplasmic reticulum (ER) stress-associated cone apoptosis, protein mislocalization, and ER calcium dysregulation. This work demonstrates a role of ER Ca2+ channel ryanodine receptor 2 and ER calcium dysregulation in protein mislocalization and subsequent ER stress and cone cell death. The findings provide novel insights into the mechanisms of photoreceptor degeneration. Altered calcium signaling and ER stress-associated cell death are common throughout retinal degenerative diseases. Thus, strategies targeting ER calcium regulation may help treat or slow photoreceptor degeneration. ER -